11q21.1‐11q23.3 Is a site of intrinsic genomic instability triggered by irradiation

The chromosome location, 11q21‐23, is linked to loss of heterozygosity (LOH) in multiple tumors including those of breast, lung, and head and neck. To examine the process of LOH induction, the H292 cell line (human muco‐epidermoid carcinoma) was irradiated or treated with anti‐CD95 antibody, and individual clones isolated through two rounds of cloning. Regions of LOH were determined by screening a suite of eight polymorphic microsatellite markers covering 11p15‐11q24 using fluorescent primers and genetic analyzer peak discrimination. LOH induction was observed extending through 11q21.1‐11q23.3 in 6/49 of clones surviving 4 Gy and 8/50 after 8 Gy. Analysis of selected clones by Affymetrix 6.0 single nucleotide polymorphism (SNP) arrays confirmed the initial assessment indicating a consistent 27.3–27.7 Mbp deletion in multiple clones. The telomeric border of LOH mapped to a 1 Mbp region of elevated recombination. Whole genome analysis of SNP data indicated that site‐restricted LOH also occurred across multiple additional genomic locations. These data indicate that 11q21.1‐11q23.3, and potentially other regions of this cell line are sites of intrinsic cell‐specific instability leading to LOH after irradiation. Such deletions may subsequently be propagated by genetic selection and clonal expansion. © 2010 Wiley‐Liss, Inc.     

Spinal algetic-tonic seizures manifesting as paroxysmal "positive" Brown-Séquard syndrome.

We report on a patient suffering from symptomatic spinal attacks in the form of a paroxysmal "positive" (algetic-tonic) Brown-Séquard syndrome. A cervical cord lesion, presumably inflammatory-demyelinating in origin, was identified as the morphological correlate of these attacks. Their pathogenesis is discussed in the light of similar case reports from the literature. For the first time, this rare type of seizure is published with a video documentation. It may deserve consideration in the differential diagnosis of otherwise unexplained paroxysmal events that present in an "epileptic" manner.     

Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life

Limbic encephalitis (LE) was described in the 1960s as a clinical-pathological syndrome in adults. Initially, the paraneoplastic form was the center of interest. An increasing number of diagnostically valuable autoantibodies in patients' sera (and cerebrospinal fluid) have been identified. Lately, the impact of non-paraneoplastic LE cases has been acknowledged. In the serum of some of these patients, antibodies against voltage-dependent potassium channels (VGKC antibodies) have been detected. The characteristic MRI course of LE patients has recently been described in detail: hippocampal swelling and T2/FLAIR signal increase are early findings. After a few months, the swelling regresses, followed by hippocampal atrophy with continuous signal increase. A general consensus on formal diagnostic criteria for all LE subsyndromes has not yet been reached. This article proposes such diagnostic criteria and formulates suggestions for treatment.     

Automated 3D MRI volumetry reveals regional atrophy differences in Rasmussen encephalitis

Purpose: Rasmussen encephalitis is a chronic immune‐mediated disease leading to unilateral atrophy on magnetic resonance imaging (MRI) and progressive neurologic deficits. Until now, quantitative parameters describing the course of the disease on MRI require manual intervention and are, therefore, time‐consuming and observer‐dependent. Furthermore, regional atrophy differences cannot be evaluated with the previously published methods. In this study we present a fully automated volumetric approach applied to serial MRI scans of 12 patients with Rasmussen encephalitis. Methods: We retrospectively analyzed 12 patients with Rasmussen encephalitis with a disease onset between 2001 and 2008. All patients underwent a total of 66 serial MRI scans including a three‐dimensional T₁ data set. The volumetric analysis was based on standard procedures of the freely available software FMRIB Software Library (FSL) and required about 45 min per scan. Furthermore, planimetric analyses were performed on 51 scans as described previously. Key Findings: The relative and absolute volume loss of the affected hemisphere was significantly higher compared to the unaffected hemisphere. Referring to regional atrophy differences our results show that the frontal lobe and the insula were preferentially involved in the atrophic process. The degree of hemispheric, parietal, and occipital atrophy was negatively correlated with the age at disease onset, indicating a more aggressive and outspread disease in young children compared to adolescents. Volumetric hemispheric ratio and planimetric hemispheric ratio correlated significantly, but planimetric hemispheric ratio underestimated the real degree of hemiatrophy, especially in patients with predominant affections outside the frontoinsular region. Significance: The volumetric analysis presented here offers a precise assessment of the disease progression in Rasmussen encephalitis in an observer‐independent and time‐efficient manner and gives an interesting insight into the course of the disease on MRI. The degree of atrophy evaluated with this method correlates with clinical parameters and is comparable to atrophy rates in patients receiving immunotherapy in preceding planimetric MRI studies.     

Extinguishing extinction: hemispheric differences in the modulation of TMS-induced visual extinction by directing covert spatial attention

The topic of spatial attention is of great relevance for researchers in various fields, including neuropsychology, cognitive neuroscience, and cognitive psychology, as well as for clinical practice. Deficits of spatial attentional arising from parietal brain damage remain largely confined to the left visual field. The mechanisms underlying this hemispheric asymmetry are still elusive. We mimicked the neuropsychological syndrome of contralesional extinction by temporarily inducing a spatial attentional bias in healthy volunteers with TMS. We investigated whether directing covert spatial attention could enhance or, more importantly, counteract the resulting behavioral deficits. Although both the left and right parietal TMS induced contralateral extinction, only left hemifield extinction following right parietal TMS was severely aggravated by a competing stimulus in the ipsilesional (right) hemifield. We put forward the hypothesis that an asymmetry with respect to the ability of detaching attention from a distractor is contributing to the right hemispheric lateralization with regard to extinction. On a broader level, we suggest that "virtual patients" might be used for evaluating neuropsychological treatment in an early stage of development, reducing the burden on actual patients.     

Autoantibodies to Munc18, cerebral plasma cells and B-lymphocytes in Rasmussen encephalitis

Rasmussen encephalitis (RE) is a rare form of severe unihemispheric epilepsy established to be an autoimmune disease. Here we demonstrate the presence of autoantibodies against Munc18-1 in 20% of patients collective with biopsy-proven RE. Intriguingly, brain biopsy specimens of these patients showed a striking perivascular accentuated infiltration of B-lymphocytes and plasma cells, suggesting a subgroup of RE patients harboring Munc18-1 antibodies and concomitant B- and plasma cell infiltration.     

Diagnostik, Therapie und Verlauf der Rasmussen-Enzephalitis

Zusammenfassung   Die Rasmussen-Enzephalitis (RE) ist eine chronisch-entzündliche Erkrankung, die eine der beiden Gro?hirnhemisph?ren meist von Kindern bef?llt und diese in einem Monate bis Jahre dauernden Krankheitsprozess zerst?rt. Die Patienten leiden an h?ufigen und pharmakoresistenten Anf?llen, oft in Form einer Epilepsia partialis continua. W?hrend das Volumen der betroffenen Hemisph?re abnimmt, verschlechtern sich zunehmend die von dieser Hirnh?lfte getragenen neurologischen Funktionen. Es resultiert ein Residualstadium mit meist hochgradiger Hemiparese, einer Hemianopsie, einer kognitiven Einschr?nkung und – bei Befall der sprachdominanten Hemisph?re – einer Aphasie. Eine frühe Diagnose nach jüngst etablierten internationalen Kriterien erm?glicht den frühen Beginn einer Immuntherapie mit dem Ziel, den chronischen Abbau zu verhindern. In „ausgebrannten“ F?llen mit pharmakoresistenten Anf?llen ist die Hemisph?rektomie oder eine ihrer modernen Varianten das Therapieverfahren der Wahl mit einer hohen Chance auf postoperative Anfallsfreiheit. Dieser Beitrag fasst die gegenw?rtigen Empfehlungen zum diagnostischen und therapeutischen Vorgehen bei der RE zusammen.      

The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy

Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiac-specific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-alpha content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.     

Distinct isoforms of phospholipase A2 mediate the ability of Salmonella enterica serotype typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils

Salmonella spp. and Shigella spp. are responsible for millions of cases of enteric disease each year worldwide. While these pathogens have evolved distinct strategies for interacting with the human intestinal epithelium, they both induce significant proinflammatory responses that result in massive transepithelial migration of neutrophils across the intestinal mucosa. It has previously been shown with Salmonella enterica serotype Typhimurium that the process of neutrophil transmigration is mediated in part by the secretion of hepoxilin A(3) (HXA(3); 8-hydroxy-11,12-epoxy-eicosatetraenoic acid), a potent neutrophil chemoattractant, from the apical surface of infected model intestinal epithelium. This study confirms that HXA(3) is also secreted in response to infection by Shigella flexneri, that it is produced by a pathway involving 12/15-lipoxygenase (12/15-LOX), and that S. enterica serovar Typhimurium and S. flexneri share certain elements in the mechanism(s) that underlies the otherwise separate signal transduction pathways that are engaged to induce polymorphonuclear leukocyte (PMN) transepithelial migration (protein kinase C and extracellular signal-regulated kinases 1 and 2, respectively). PMN transepithelial migration in response to infection with S. flexneri was dependent on 12/15-LOX activity, the enzyme responsible for the initial metabolism of arachidonic acid to HXA(3). Probing further into this pathway, we also found that S. enterica serovar Typhimurium and S. flexneri activate different subtypes of phospholipase A(2), a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. Thus, although S. enterica serovar Typhimurium and S. flexneri utilize different mechanisms for triggering the induction of PMN transepithelial migration, we found that their reliance on 12/15-LOX is conserved, suggesting that enteric pathogens may ultimately stimulate similar pathways for the synthesis and release of HXA(3).